Project Summary
Vagal nerve stimulation (VNS) has emerged as a promising therapy for cardiac arrhythmia by electrical
stimulation of vagal nerve at the cervical level. Direct VNS achieves its antiarrhythmic effects through increasing
efferent parasympathetic input to the heart. However, patients receiving VNS have reported severe side effects,
which are due to off-target stimulation of non-cardiac vagal branches. Cholinergic activation using
pharmacological approaches also resulted in serious adverse events due to lack of organ specificity. Increasing
vagal efferent input to the heart by targeting cardiac vagal postganglionic (CVP) neurons alone would be ideal
to minimize the off-target effects and to achieve precision of parasympathetic activation for anti-arrhythmia. Here,
we will introduce a miniaturized bio-optoelectronic implant that avoids limitations of VNS and pharmacological
approaches by using optogenetics to treat fatal ventricular arrhythmias in type 2 diabetes mellitus (T2DM).
Comparing with electrical and pharmacological approaches, optogenetics provides higher speed and accuracy
in regulation of living cell function with less complications. However, a strategy of optogenetic therapy on
ventricular arrhythmias in T2DM has not yet been established. Withdrawal of cardiac vagal activity is associated
with ventricular arrhythmias-related sudden cardiac death and with high mortality in T2DM patients. Patients with
T2DM are two to four times more likely to die from myocardial infarction (MI), compared with non-diabetic
patients. Our recent study confirmed that reduction of cell excitability in CVP neurons exacerbates MI-evoked
ventricular arrhythmias and mortality in T2DM animals. Considering the advantages of optogenetics including
rapid, specific control of neuronal activities by light-sensitive opsins, adeno-associated virus-channelrhodopsin-
2 (AAV-ChAT-ChR2-mcherry) will be transfected into CVP neurons in T2DM animals. Specificity of neuronal
expression of ChR2 (an excitatory light-sensitive opsin) in CVP neurons will be achieved by linking the choline
acetyltransferase (ChAT, a specific marker of cholinergic neurons) promoter to the ChR2 gene. Continual
optogenetic stimulation in CVP neurons will be achieved by illuminating a light-emitting-diodes (LED) probe that
is controlled and powered wirelessly in freely moving animals. We hypothesize that optogenetic therapy could
restore cell excitability of CVP neurons and acetylcholine (ACh) release from cardiac vagal nerve
terminals, further improve vagal control of ventricular function and reduce acute MI-evoked ventricular
arrhythmias and high mortality in T2DM. To test this hypothesis, we will determine if optogenetic restoration
in CVP neuronal excitability restores ACh release from cardiac vagal nerve terminals, improves vagal control of
ventricular function, and reduces MI-evoked fatal ventricular arrhythmias and high mortality in T2DM animals.
This proposal will establish the first evidence of the optogenetic therapy on MI-evoked ventricular arrhythmias
and mortality in T2DM, and may provide a new therapeutic strategy for improving outcomes and quality of life in
T2DM patients.